Treatments for Spasticity and Pain in Multiple Sclerosis: A Systematic Review PDF

Health Technology Assessment 2003; Vol. 7: No. 40 Treatments for spasticity and pain in multiple sclerosis: a systematic review S Beard A Hunn J Wight Health Technology Assessment NHS R&D HTA Programme HTA  HTA How to obtain copie...

Health Technology Assessment 2003; Vol. 7: No. 40 Treatments for spasticity and pain in multiple sclerosis: a systematic review S Beard A Hunn J Wight Health Technology Assessment NHS R&D HTA Programme HTA  HTA How to obtain copies of this and other HTA Programme reports. An electronic version of this publication, in Adobe Acrobat format, is available for downloading free of charge for personal use from the HTA website (http://www.hta.ac.uk). A fully searchable CD-ROM is also available (see below). Printed copies of HTA monographs cost £20 each (post and packing free in the UK) to both public and private sector purchasers from our Despatch Agents. Non-UK purchasers will have to pay a small fee for post and packing. For European countries the cost is £2 per monograph and for the rest of the world £3 per monograph. 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The website also provides information about the HTA Programme and lists the membership of the various committees. Treatments for spasticity and pain in multiple sclerosis: a systematic review S Beard A Hunn J Wight School of Health and Related Research (ScHARR), University of Sheffield, UK Declared competing interests of authors: none Published December 2003 This report should be referenced as follows: Beard S, Hunn A, Wight J. Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess 2003;7(40). Health Technology Assessment is indexed in Index Medicus/MEDLINE and Excerpta Medica/ EMBASE.  NHS R&D HTA Programme T he NHS R&D Health Technology Assessment (HTA) Programme was set up in 1993 to ensure that high-quality research information on the costs, effectiveness and broader impact of health technologies is produced in the most efficient way for those who use, manage and provide care in the NHS. The research reported in this monograph was commissioned by the HTA Programme and funded as project number 99/05/03. Technology assessment reports are completed in a limited time to inform decisions in key areas by bringing together evidence on the use of the technology concerned. The views expressed in this publication are those of the authors and not necessarily those of the HTA Programme or the Department of Health. The editors wish to emphasise that funding and publication of this research by the NHS should not be taken as implicit support for any recommendations made by the authors. Criteria for inclusion in the HTA monograph series Reports are published in the HTA monograph series if (1) they have resulted from work commissioned for the HTA Programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors. Reviews in Health Technology Assessment are termed ‘systematic’ when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. HTA Programme Director: Professor Kent Woods Series Editors: Professor Andrew Stevens, Dr Ken Stein, Professor John Gabbay, Dr Ruairidh Milne, Dr Chris Hyde and Dr Rob Riemsma Managing Editors: Sally Bailey and Sarah Llewellyn Lloyd The editors and publisher have tried to ensure the accuracy of this report but do not accept liability for damages or losses arising from material published in this report. ISSN 1366-5278 © Queen’s Printer and Controller of HMSO 2003 This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to HMSO,The Copyright Unit, St Clements House, 2–16 Colegate, Norwich, NR3 1BQ. Published by Gray Publishing, Tunbridge Wells, Kent, on behalf of NCCHTA. Printed on acid-free paper in the UK by St Edmundsbury Press Ltd, Bury St Edmunds, Suffolk. O2  Health Technology Assessment 2003; Vol. 7: No. 40 Abstract Treatments for spasticity and pain in multiple sclerosis: a systematic review S Beard, A Hunn and J Wight School of Health and Related Research (ScHARR), University of Sheffield, UK Objectives: To identify the drug treatments currently designed specifically to evaluate the alleviation of pain available for the management of spasticity and pain in in patients with MS and there was no consistency multiple sclerosis (MS), and to evaluate their clinical and regarding the use of validated outcome measures. It cost-effectiveness. was suggested that, although expensive, the use of Data sources: Electronic bibliographic databases, intrathecal baclofen may be associated with significant National Research Register, MRC Clinical Trials Register savings in hospitalisation costs in relation to bed-bound and the US National Institutes of Health Clinical Trials patients who are at risk of developing pressure sores, Register. thus enhancing its cost-effectiveness. No studies of Review methods: Systematic searches identified 15 cost-effectiveness were identified in the review interventions for the treatment of spasticity and 15 of pain. There is evidence, albeit limited, of the interventions for treatment of pain. The quality and clinical effectiveness of baclofen, dantrolene, outcomes of the studies were evaluated. Reviews of diazepam, tizanidine, intrathecal baclofen and BT the treatment of spasticity and pain when due to other and of the potential cost-effectiveness of intrathecal aetiologies were also sought. baclofen in the treatment of spasticity Results: There is limited evidence of the effectiveness in MS. of four oral drugs for spasticity: baclofen, dantrolene, Conclusions: Many of the interventions identified are diazepam and tizanidine. Tizanidine appears to be no not licensed for the alleviation of pain or spasticity in more effective than comparator drugs such as baclofen MS and the lack of evidence relating to their and has a slightly different side-effects profile. Despite effectiveness may also limit their widespread use. claims that it causes less muscle weakness, there was Indeed, forthcoming information relating to the use of very little evidence that tizanidine performed any cannabinoids in MS may result in there being better better in this respect than other drugs, although it is evidence of the effectiveness of new treatments than of more expensive. The findings of this review are any of the currently used drugs. It may therefore be of consistent with reviews of the same treatments for value to carry out double-blind randomised controlled spasticity derived from other aetiologies. There is good trials of interventions used in current practice, where evidence that both botulinum toxin (BT) and intrathecal outcomes could include functional benefit and impact baclofen are effective in reducing spasticity, and both on quality of life. Further research into the are associated with functional benefit. However, they development and validation of outcomes measures for are invasive, and substantially more expensive. None of pain and spasticity may also be useful, as perhaps would the studies included in the review of pain were cost–utility studies. iii © Queen’s Printer and Controller of HMSO 2003. All rights reserved.  Health Technology Assessment 2003; Vol. 7: No. 40 Contents List of abbreviations.................................. vii 5 Pain in MS.................................................. 75 Scope of review........................................... 75 Executive summary.................................... ix Prevalence.................................................. 75 Types of pain syndromes (and difficulties in 1 Aim and background................................. 1 defining and dissociating them)................ 75 Aim of the report....................................... 1 Current clinical practice............................. 78 Background................................................ 1 Epidemiology............................................. 1 6 Review of the treatment of pain in MS: Symptoms................................................... 1 methods..................................................... 81 Structure of this report............................... 2 Formal scoping review................................ 81 2 Spasticity in MS......................................... 3 7 Review of the treatment of pain in MS: Nature and aetiology of spasticity in MS... 3 results......................................................... 83 Epidemiology of spasticity in MS.............. 3 Scope and quality of research evidence..... 83 Impact and prognosis of spasticity in MS.. 3 Drugs considered....................................... 83 Current service provision........................... 3 Outcome measures..................................... 83 Criteria for treatment................................. 4 Specific drug treatments............................ 83 Other treatments for pain in MS............... 90 3 Review of treatments for spasticity: Discussion................................................... 90 methods..................................................... 5 Conclusions................................................ 91 Formal scoping review................................ 5 Inclusion criteria........................................ 5 8 Implications for future research................ 93 Quality assessment strategy....................... 5 Methods of analysis and synthesis............. 6 Acknowledgements.................................... 95 4 Results of the systematic review of References.................................................. 97 treatments for spasticity in MS................. 7 Description of the interventions Appendix 1 Jadad scale for assessing the considered.................................................. 7 quality of published research..................... 103 Existing reviews.......................................... 7 Oral baclofen (Lioresal)............................. 7 Appendix 2 Outcome measures and rating Dantrolene (Dantrium).............................. 17 scales........................................................... 105 Tizanidine (Zanaflex, Sirdalud)................. 23 Diazepam................................................... 34 Appendix 3 Search strategies.................... 107 Gabapentin (Neurontin)............................ 41 Progabide (halogabide).............................. 44 Health Technology Assessment reports BT (Botox, Dysport)................................... 46 published to date....................................... 113 Intrathecal baclofen................................... 52 Phenol........................................................ 61 Health Technology Assessment Threonine................................................... 64 Programme................................................ 121 Vigabatrin................................................... 64 Economic evidence..................................... 66 Discussion and conclusions........................ 70 v  Health Technology Assessment 2003; Vol. 7: No. 40 List of abbreviations ACTH adrenocorticotrophic MHI Mental Health Inventory ADL activities of daily living MRC Medical Research Council AMB ambulation index MS multiple sclerosis BT botulinum toxin MSIS MS Impairment Scale CCS chronic cerebellar stimulation NICE National Institute for Clinical Excellence CIBI continuous intrathecal baclofen infusion NRS Neurologic Rating Scale CNS central nervous system NSAID non-steroidal anti-inflammatory drug CSF cerebrospinal fluid QoL quality of life DSS Disability Status Scale RCT randomised controlled trial DB double blind SCI spinal cord injury DREZ dorsal root entry zone SF-36 Short Form with 36 Items EDSS Expanded Disability Status Scale SIP Sickness Impact Profile EMG electromyographic TAA turn/amplitude analysis GABA -aminobutyric acid TENS transcutaneous electrical nerve stimulation IHQL Index of Health Related Quality of Life TGN trigeminal neuralgia All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table. vii © Queen’s Printer and Controller of HMSO 2003. All rights reserved.  Health Technology Assessment 2003; Vol. 7: No. 40 Executive summary Background baclofen (Lioresal) dantrolene (Dantrium) Multiple sclerosis (MS) is one of the commonest tizanidine (Zanaflex) neurological conditions of young adults in the diazepam Western world, with an estimated 58,000–63,000 gabapentin (Neurontin) people with the disease in England and Wales. Pain botulinum toxin (BT) (Botox, Dysport) and spasticity are two of the commonest symptoms intrathecal baclofen (Lioresal Intrathecal) from which people with MS suffer. A recent survey phenol of members by the MS Society found that 54% threonine reported pain as a current symptom and 74% vigabatrin spasticity. The importance of these symptoms is not clonidine simply because of their frequency, but also because methylprednisone of the impact they have on daily life. As the disease cyproheptadine progresses, so does the spasticity, resulting in magnesium muscle spasms, immobility, disturbed sleep and ketazolam. pain. Disability resulting from spasticity can lead to patients requiring extensive nursing care. Sixty-seven papers, 41 of which were described as double-blind randomised controlled trials (RCTs), Pain can be caused by a variety of factors including were included in the review of spasticity. Overall, spasticity itself, in addition to neuronal damage the quality of the studies was poor. A wide variety due to the disease process. Not uncommonly, it of outcome measures were used. In cases where may be musculoskeletal in origin, arising as a the same outcome measures were used, there were result of abnormal posture following the disability inconsistencies in the application of instruments caused by MS. and analysis of results across studies. There is limited evidence of the effectiveness of Methods four oral drugs for spasticity: baclofen, dantrolene, diazepam and tizanidine. All appear to be A systematic review was undertaken to identify approximately equally effective at reducing what treatments are available for the management spasticity when assessed clinically, although in no of pain and spasticity in MS and to evaluate case is there any good evidence of functional clinical and cost effectiveness through assessment benefit. Tizanidine appears to be no more of the best available evidence. The scope of the effective than comparator drugs such as baclofen. review was limited to the consideration of drug Tizanidine has a slightly different side-effects treatments. It did not include non-drug therapy or profile in that the main side-effect of tizadine is a surgical treatments. It did not consider dry mouth. Despite claims that it causes less cannabinoids, clinical trials of which were ongoing muscle weakness, there was very little evidence at the time of the review. Reviews of the treatment that tizanidine performed any better in this of spasticity and pain when due to other respect than other drugs, although it is more aetiologies were also sought and their conclusions expensive. The findings of this review are were examined for consistency with the consistent with reviews of the same treatments for conclusions in the primary studies identified. spasticity derived from other aetiologies. There is no good evidence of effectiveness for Results gapapentin, threonine, vigabatrin, methylprednisolone, cyprohepladine or Spasticity magnesium. Systematic searches for evidence relating to the treatment of spasticity identified 15 interventions There is good evidence that both BT and for inclusion: intrathecal baclofen are effective in reducing ix © Queen’s Printer and Controller of HMSO 2003. All rights reserved.  Executive summary spasticity, and both are associated with functional although expensive, the use of intrathecal baclofen benefit. However, they are invasive, and may be associated with significant savings in substantially more expensive. Their use is most hospitalisation costs in relation to bed-bound appropriately restricted to people with severe patients who are at risk of developing pressure disabling spasticity. sores, thus enhancing its cost-effectiveness. No studies of cost-effectiveness were identified in the Pain review of pain. Systematic searches for evidence relating to the treatment of pain identified 15 interventions: There is evidence, albeit limited, of the clinical effectiveness of baclofen, dantrolene, diazepam, carbamazepine tizanidine, intrathecal baclofen and BT and phenytoin of the potential cost-effectiveness of intrathecal gabapentin baclofen in the treatment of spasticity in MS. lamotrigine Owing to the paucity and poor quality of evidence tricyclic antidepressants identified in this review, no further conclusions steroids regarding the clinical or cost-effectiveness of the baclofen remaining interventions for pain or spasticity can intrathecal baclofen be drawn. amantadine misoprostol octreotide Conclusions bupivacaine acetazolamide Many of the interventions identified are not lidocaine licensed for the alleviation of pain or spasticity mexiletine. in MS. In addition, the lack of evidence relating to their effectiveness may militate against them Thirty-three studies were included in the review of being used consistently across the NHS. Lastly, pain. None of the studies were RCTs designed the licensing and forthcoming availability of specifically to evaluate the alleviation of pain in trial evidence relating to the use of cannabinoids patients with MS. The majority of papers were in the alleviation of symptoms relating to MS may non-systematic reviews, small case series or mean that we are in the ironic position of having individual case reports. There was no consistency better evidence of the effectiveness of new regarding the use of validated outcome measures. treatments than of any of the currently used Most papers recorded only that pain had or had drugs. not been relieved. Cost-effectiveness and clinical Recommendations for research effectiveness In the absence of formal research of any quality in The following areas are suggested for further this area, it is not possible to draw conclusions research: regarding the effectiveness or otherwise of the interventions identified. Double-blind RCTs, with adequate power and follow-up, of interventions used in current Evidence relating to the cost-effectiveness of practice for the alleviation of pain and spasticity treatments was extremely limited. In the review of in MS. Outcomes should include functional spasticity, five health economic evaluations of benefit and impact on quality of life. intrathecal baclofen were identified. No studies Development and validation of outcomes relating to the remaining treatments were measures for pain and spasticity. identified. The five studies suggested that Cost–utility studies. x  Health Technology Assessment 2003; Vol. 7: No. 40 Chapter 1 Aim and background Aim of the report MS is twice as common in women than men. There is evidence that patients with MS are This report addresses two questions: starting to live longer1 and this will have implications for the number of patients What are the treatments currently available for experiencing severe spasticity. the management of spasticity and pain in multiple sclerosis (MS)? What is the clinical and cost-effectiveness of Symptoms each of these treatments for spasticity and pain in MS? The progression of the disease is extremely variable. While initially the disease may be The purpose of this report is to provide a wider relapsing and remitting, it usually becomes perspective of the needs and potential progressive over time, resulting in chronic interventions in MS. It is not possible to cover disability. The signs and symptoms of MS are each individual treatment in great depth. variable, but generally reflect the degree of Treatments other than drug therapy are not within demyelination that has taken place. The main the remit of this report. presenting symptoms of MS are:2 weakness in one or more limbs optic neuritis Background paraesthesiae The treatment of MS has been identified by the diplopia National Institute for Clinical Excellence (NICE) vertigo as an important area for evaluation. There is no disturbance of micturition. cure, and treatments currently available are directed towards slowing the progression of As the disease progresses, other symptoms become disease, reducing relapses or alleviating the wide more significant. A recent survey by the MS spectrum of symptoms. This report is part of a Society of 275 members (all patients with series evaluating the effectiveness and cost- established MS) reported fatigue, spasticity effectiveness of interventions for MS. (stiffness, spasms or both) and problems with balance as the most commonly experienced MS is an inflammatory disease, which results in symptoms (233 responses received – a rate of myelin loss in the central nervous system (CNS). 80%).3 Results are summarised in Table 1. This in turn leads to the development of sclerotic patches known as plaques in the brain and spinal Recently, attention has focused on new drugs for cord. Although the aetiology is unknown, there is slowing disease progression and reducing relapses. strong evidence that MS is the result of an However, the identification of effective drugs for autoimmune response. the alleviation of symptoms remains very important. Spasticity and pain are two of the most important symptoms experienced by suffers of Epidemiology MS, both because of their frequency, but also because of the impact on daily life. As the disease MS is one of the most common neurological progresses, so does the spasticity, resulting in conditions affecting young adults in the Western muscle spasms, immobility, disturbed sleep and world. The prevalence of MS in England and pain. Disability resulting from spasticity can lead Wales is around 110–120 per 100,000, although to patients requiring extensive nursing care. this varies geographically, with a higher prevalence in the north of England.1 This translates to Pain can be caused by a variety of factors, including between 58,000 and 63,000 cases for England and spasticity itself, in addition to neuronal damage. Wales, although some estimates have been higher. Not uncommonly it may be musculoskeletal in 1 © Queen’s Printer and Controller of HMSO 2003. All rights reserved.  Aim and background TABLE 1 Results of the MS Society survey Symptom % currently experiencing symptom % rating symptom as one of (top 8) three worst (top 8) Fatigue 86 65 Bladder or bowel problems 66 50 Balance problems 73 44 Muscle weakness 69 44 Visual problems Not available 20 Pain 54 18 Muscle stiffness 64 17 Muscle spasms 51 14 Spasticity (stiffness or spasm or both) 74 Not available Numbness/tingling 64 Not available origin, arising as a result of abnormal posture treatment, then the methods and findings of the following the disability caused by MS. review are reported. A review, limited by the amount of available evidence, of the economic aspects of the treatment of spasticity is included. Structure of this report There is no economic review of the treatment of pain, as no literature was identified relating to This report contains two separate reviews: one of this. Overall, there was substantially more primary the effectiveness and cost-effectiveness of literature identified dealing with the treatment of treatment for spasticity in MS and the other of spasticity than of pain, and this is reflected in the treatment for pain. In each case, the problem is relative length and in the structure of reporting of described, followed by what is known of current the two reviews. 2  Health Technology Assessment 2003; Vol. 7: No. 40 Chapter 2 Spasticity in MS Nature and aetiology of spasticity Epidemiology of spasticity in MS in MS Spasticity has been estimated to affect between 40 Spasticity, or increased tone, is a motor disorder and 60% of all patients with MS. In the MS Society caused by lesions of the CNS involving the upper survey undertaken in October 1997,3 64% of motor neurones. It is associated with sprouting of respondents reported muscle stiffness and 51% descending motor pathways to form new muscle spasms. Overall, 74% reported stiffness, synaptic connections with spinal neurones and spasms or both. However, although the response with denervation hypersensitivity. It is more rate of 80% was high, it is likely that both the less, common in the lower limbs. in addition to the more, disabled patients were excluded. Nevertheless, it does give an indication Spasticity is a major contributor to disability in as to the scale of the problem. MS. It can cause pain, inability to walk and, later, problems with personal hygiene. Indeed, it is spasticity rather than weakness in the limbs which Impact and prognosis of accounts for much of the disability affecting lower spasticity in MS limbs. It is difficult to be precise about the prognosis of The severity of spasticity increases as the disease MS since the evidence is poor. Surveys indicate progresses. Initially increased tone may be that approximately 50% of patients with MS are manifest as extensor spasms. These are independent and still able to walk after 15 years. particularly likely to occur at night or on A review of survival studies by Compston and waking in the morning. They may be so severe Swinglar indicates that some 75% of patients as to eject the patient from a wheelchair. survive for 25 years.4 Nevertheless, severe The legs are held rigidly extended for several spasticity can result in complete immobility. It is minutes. not known how many MS patients enter the helpless bedridden stage.2 However, as the disease progresses, the spasticity begins to affect the flexor tone, which initially Although the authors were not able to identify any results in the patient falling over unexpectedly. In peer-reviewed literature concerning the impact of contrast to sudden extension, flexor spasms are spasticity on the quality of life (QoL) of patients frequently painful. Over time, the flexed posture with MS, a poster presented at an MS Society can become more frequent and eventually conference5 reported on the Short Form with 36 permanent. The increased muscle tone eventually Items (SF-36) scores of 174 people with spasticity leads to difficulties in nursing care and in related to MS. This suggested a clear reduction, maintaining hygiene. In some cases this can lead with increasing spasticity, in SF-36 scores in all to bed sores, which in turn exacerbate the muscle except the ‘role physical’ dimension. Interestingly, spasms. It is important to bear in mind that in this sample, 41% of respondents claimed never spasticity can be a useful function in the earlier to have seen a neurologist, 56% never to have seen stages of the disease, particularly whilst the patient a specialist in a rehabilitation centre and 60% never is still ambulatory, and may assist the patient in to have seen an MS or neurology specialist nurse. standing. However, the need to treat spasticity increases as the disease progresses. In non- ambulatory patients the spasticity can become Current service provision painful and problematic, making transfer of the patient difficult and causing problems for the It was not possible to identify any formal review of carers of patients, particularly in maintaining current clinical practice regarding the treatment of hygiene. spasticity in MS. Anecdotal reports suggest that it 3 © Queen’s Printer and Controller of HMSO 2003. All rights reserved.  Spasticity in MS may be very variable. The MS Society survey on this. The use of CIBI appears to be low; for referred to above reported that 32% of patients instance, in 1998 in the whole of Britain, around did not see a hospital specialist for treatment.3 200 patients were implanted with a pump for Reasons varied from patient unhappiness with intrathecal baclofen, of whom only around 60 had previous experience of hospital specialists to MS.6 This is likely also to be true of the general practitioners (GPs) telling them ‘that intramuscular botulinum toxin (BT) injection, nothing can be done for MS’. The survey also which it should be noted is not licensed for this found that overall 37% of patients had taken indication. baclofen, 9% diazepam and 2% dantrolene in the previous 2 years. No information was available for any other antispastic drugs. Of those who had Criteria for treatment taken baclofen, 42% had had side-effects, most commonly weakness. When considering treatments for spasticity, it is important to recognise that the desired effect may Current clinical reviews of treatment suggest that change over time as the disease progresses. It is the standard treatment for moderate spasticity is necessary to distinguish between the less severe oral therapy including baclofen, dantrolene, spasticity in the early stages of MS when the diazepam and, more recently, tizanidine. patient will still be ambulant and more severe Sometimes, combinations of these therapies are spasticity in the advanced stages of MS when the used. Pharmacological interventions are usually patient may be non-ambulant. supported by physiotherapy; however, the effectiveness of physiotherapy has not been Treatment for spasticity aimed at reducing muscle assessed in this review. MS requires a multi- tone may achieve this at the expense of increased disciplinary team approach bringing together weakness. This, in turn, can lead to no neurologists, physiotherapy and nursing care. improvement in function or even a deterioration Physiotherapy in particular is used to develop a of function. Spasticity itself can be helpful to an programme of stretching and range-of-motion ambulant patient and treatment is only necessary exercises. when the spasticity becomes a problem. It has been suggested that some GPs may be In the early stages of the disease, patients who are reluctant to prescribe the more expensive still ambulant will usually receive oral drugs. antispastic drugs (e.g. tizanidine), though no However, in non-ambulant patients, there may be evidence has been put forward to substantiate this. greater emphasis on increasing comfort and The average daily cost of tizanidine is more than facilitating nursing care even if this results in twice that of baclofen. Access to more invasive greater muscle weakness and less mobility. treatment, in particular, continuous intrathecal Injectable or intrathecal drugs are more likely to baclofen infusion (CIBI), appears to be extremely be given to non-ambulant patients. Once a patient variable and depends on the availability of the becomes unresponsive to oral therapy, then the service and local clinical practice. Again, there choices are limited to CIBI or intramuscular does not appear to be any systematic information injections of BT. 4  Health Technology Assessment 2003; Vol. 7: No. 40 Chapter 3 Review of treatments for spasticity: methods Formal scoping review NHS CRD HTA (Health Technology Assessment). The aim of the search was to identify treatments for inclusion in the review, and to locate relevant Search strategies for MEDLINE are given in randomised controlled trials (RCTs), reviews and Appendix 3. Search strategies for other databases cost-effectiveness studies. are available from the authors. Initial scoping searches were conducted to identify In addition to searches of electronic bibliographic references relating to MS and spasticity. The main databases, sources were consulted to identify aims of the initial searches were twofold: to identify studies not retrieved through database searching, interventions to contribute to the framework of current research and grey literature. The National treatments considered in the review; and to Research Register (NRR), MRC Clinical Trials identify search terms to inform the development Register and the US National Institutes of Health of further, comprehensive search strategies. (NIH) Clinical Trials Register were searched. The Therefore, search strategies at this stage were publication lists and current research registers of designed to optimise the specificity of the search health technology assessment and guideline- results. The searches were undertaken in January producing agencies and funding and regulatory 2000 on MEDLINE, EMBASE and the Science bodies were consulted. Searches were repeated in Citation Index. Search results were not limited by March 2002. date, language or by study or publication type. Comprehensive search strategies were then Inclusion criteria constructed to identify papers relating to MS and the individual treatments for spasticity. Search In selecting studies to be included in this review, results were not restricted by date, but were the following criteria were used: restricted to English language. Filters to limit search results to RCTs, reviews or cost-effectiveness at least 50% of the trial subjects had to be studies were applied. Searches were undertaken in diagnosed as having MS or June and July 2000 on the following databases: if less than 50% of subjects had MS, then the findings for the MS patients had to be MEDLINE presented separately. EMBASE Science Citation Index The inclusion criteria regarding study design were CDSR (Cochrane Database of Systematic based on ‘best available’ evidence. Where possible, Reviews) the review was restricted to RCTs. However, this CENTRAL/CCTR (Cochrane Controlled Trials was not always possible owing to lack of RCT Register) evidence in which case studies of weaker design PubMed were included. Details are given in individual HealthSTAR chapters. Best Evidence CINAHL (Cumulative Index of Nursing and Allied Health Literature) Quality assessment AMED (Allied and Complementary Medicine) strategy NHS CRD DARE (Database of Abstracts of Reviews of Effectiveness) The Jadad scale was used for assessing the quality NHS CRD NHS EED (NHS Economic of the papers selected for inclusion in this review.7 Evaluation Database) Details are given in Appendix 1. 5 © Queen’s Printer and Controller of HMSO 2003. All rights reserved.  Review of treatments for spasticity: methods Methods of analysis and specifically considered. Direction of effect was summarised. It was not possible to carry out a synthesis meta-analysis of the findings since there was a The data were analysed by drug and summarised wide variety of outcome measures employed and, in a tabular format. Validity of outcome measures, even where the same outcome measure was validity of design and statistical analysis were employed, it was often in incompatible forms. 6  Health Technology Assessment 2003; Vol. 7: No. 40 Chapter 4 Results of the systematic review of treatments for spasticity in MS Description of the interventions Oral baclofen (Lioresal) considered Baclofen is a -aminobutyric acid (GABA) This review considers drug treatments for derivative which, unlike the parent compound, spasticity and does not include non-drug therapy crosses the blood–brain barrier, albeit to a limited or surgical treatments. The drug treatments which extent. GABA is a major inhibitor of impulse are considered are: transmission in the nervous system, and baclofen is thought to exert an antispastic effect through baclofen (Lioresal) inhibiting reflex neurological transmissions in the dantrolene (Dantrium) spinal cord via its effect on GABA receptors. The tizanidine (Zanaflex) cost of baclofen is £10.84 for 84 5-mg tablets.10 diazepam The maximum daily dose is 100 mg. At this gabapentin (Neurontin) dosage, the average daily cost of oral baclofen botulinum toxin (Botox, Dysport) would be £2.58. intrathecal baclofen (Lioresal Intrathecal) phenol Quantity of research available threonine The search strategy identified 16 papers. Four of vigabatrin these were excluded, two because they did not clonidine include patients with MS, one because, although it methylprednisone did include MS patients, they were fewer than half cyproheptadine of all the patients and results were not shown magnesium separately, and one because it was a second ketazolam. publication of the same study with a different lead author. This review excludes cannabinoids, although anecdotal evidence suggests they may be effective Eleven randomised and one non-randomised at treating both spasticity and pain. Clinical trials double-blind (DB) controlled trials of the effect of are in progress to evaluate their role. baclofen on spasticity were identified. Nine (including the non-randomised study) were comparisons with placebo, three with diazepam. One of the latter also reported comparison with Existing reviews placebo. In this one, the evaluating physician In addition to this review, two published systematic would not have been blind to the placebo reviews relating to drug treatment for spasticity comparison (and it is not altogether clear that the were identified. A Cochrane review, last updated patients would have been either). One of these in June 2001, identified 23 placebo-controlled studies also involved assessing the effect of the trials on antispasticity agents for MS8 and Creedon drug on muscle strength, and this was reported and colleagues carried out a meta-analysis of separately. Nine were crossover studies, two intrathecal baclofen in 1997.9 This took the form parallel group studies, and in one it was not clear. of a meta-analysis of English language trials of Study details are summarised in Tables 2 and 3. published studies on intrathecal baclofen prior to June 1996 and covered 27 studies including 162 Populations examined patients with MS. There were also various reviews Seven of the studies recruited exclusively patients of single antispasticity agents in non-MS with MS, described variously as ‘established’ or conditions which have been referred to in the ‘clinically definite’. In the others the majority of discussion. patients had MS. The age range where stated was 7 © Queen’s Printer and Controller of HMSO 2003. All rights reserved. 8 TABLE 2 Baclofen vs placebo Results of the systematic review of treatments for spasticity in MS Study Design Drugs and dose Patients Withdrawals Outcomes Results Trial measured quality (Jadad) Jerusalem DB parallel Baclofen 16 patients, N = 30. None Four grades of success Success reported in 12/16 3/5 (1968), group RCT, placebo 14. Baclofen 29 with MS, one with identified (none, slight, patients on baclofen, 5/14 on Germany19 single centre titrated up to syringomyelia. good, very good) placebo. Difference reported 80 mg/day. Duration not Non-progressive for according to change on to be ‘statistically significant’. explicit (>8 days). 6 months. Majority an ad hoc five-point Night spasms helped in 8/9 All had exercise and housebound, none scale patients. hydrotherapy bedridden Of 25 patients in total who took baclofen (including patients transferred from placebo), 7 reported sedation, 5 weakness (leading to reduction in dose), 1 nausea, 1 dry mouth Hudgson DB crossover Baclofen 30 mg/day for N = 23. None Assessment of spasticity Degree of improvement in 4/5 et al. (1971), RCT, single 10 days, placebo 7 days, 18 with MS. using Ashworth scale, at spasticity greater on baclofen UK14,20 centre washout Aged 30–63 y. the start and finish of than placebo in 16 patients, 16 M, 7 F. baclofen and placebo greater on placebo than All had spasticity graded treatment. baclofen in 7 patients. Mean at 3–4/4 on the change in score was 1.44 on Ashworth scale baclofen, 0.54 on placebo (p < 0.05). Subjective assessment 13 patients said stiffness reduced on baclofen, 5 on placebo, 5 reported no difference. Side-effects (mild nausea) in 6 patients on baclofen, 3 on placebo continued  TABLE 2 Baclofen vs placebo (cont’d) © Queen’s Printer and Controller of HMSO 2003. All rights reserved. Study Design Drugs and dose Patients Withdrawals Outcomes Results Trial measured quality (Jadad) Basmajian DB crossover Baclofen (dose not N = 14. N = 3, ‘for personal Not stated Baclofen superior in 7/11 4/5 (1975), RCT, single specified) for 4 weeks, All with MS. reasons unrelated to patients, placebo superior USA21 centre placebo for 4 weeks, Aged 21–55 y. therapy’ in 3/11. 1 week washout MS with spasticity for When 8 additional patients >3 months from an earlier study are included, baclofen was superior in a total of 9/19, placebo superior in 5/19, and neither drug superior in 5/19. No information on-side effects Levine et al. DB controlled Baclofen increasing N = 19. N = 1; however, all Muscle hypertonicity 53% drop in MSV on baclofen, 2/5 (1977), trial, possibly 15–80 mg/day on Average age 43 y. patients did not using EMG. 5% on placebo. USA16 crossover predetermined 5 F, 12 M. complete all tests Measurements of 82% of MS patients had (does not schedule. 12 had MS. change in MSV >30% fall in MVS on baclofen, appear to Placebo. Patients were all (microvolt seconds) compared with 21% on have been Treatment for 5 weeks, severely disabled, before and after the test placebo. randomised) washout for 3 weeks confined either to bed drug. or wheelchair No statistical analysis. Health Technology Assessment 2003; Vol. 7: No. 40 Clinical grading score No difference to placebo, but (CLN) analysis is unclear. Baclofen was well tolerated and any side-effects seem to be dose related continued 9 10 TABLE 2 Baclofen vs placebo (cont’d) Results of the systematic review of treatments for spasticity in MS Study Design Drugs and dose Patients Withdrawals Outcomes Results Trial measured quality (Jadad) Sachais et al. DB parallel Baclofen titrated up to N = 166. Baclofen N = 31, Subjective neurological Statistically significant 3/5 (1977), group RCT at a maximum of Spasticity secondary to placebo N = 29, examination difference in decreases from USA22 16 centres 70–80 mg/day on a MS receiving inpatient excluded from statistical baseline values in pain and predetermined or outpatient care. analysis for protocal frequency of flexor spasms, schedule. Minimum age 18, violation, primarily resistance to passive joint Placebo. mean 43 y. related to concomitant movement in the ankle flexion, Treatment for 5 weeks Baclofen 85 patients, use of disallowed knee flexion and extension and placebo 81 medications, tendon stretch reflexes in the relationship with side- knee. effects not specified Physician assessment of Overall spastic state improved clinical change. ( p < 0.001). Patient self-evaluation Muscle spasms and clonus improved ( p < 0.005) Feldman DB crossover Baclofen increasing N = 33. N = 10, due to non- Resistance to passive 15/23 improved on baclofen, 3/5 et al. (1978), RCT (long- 15–80 mg/day. Age 38–53 y. compliance, intercurrent movement. 4/23 on placebo (p < 0.05). USA18 term follow- Placebo. M:F not stated. illness, inability to Spasm frequency. 9/23 improved on baclofen, up not 4 weeks on each Established diagnosis of tolerate worsening 1/23 on placebo (p < 0.05). reported treatment MS with spasticity for at symptoms here) least 3 months. Clonus. 12/23 improved on baclofen, Duration of MS 3–30 y. 1/23 on placebo (p < 0.001). Disability varied Barthel index. No significant difference between ambulatory with spastic gait to Ambulation. No significant difference quadriplegic Transfer activity. No significant difference Subjective rating of limb No significant difference pain. Use of spastic limb No significant difference Side-effects of baclofen included drowsiness, dry mouth, paresthesia and blurred vision continued  TABLE 2 Baclofen vs placebo (cont’d) © Queen’s Printer and Controller of HMSO 2003. All rights reserved. Study Design Drugs and dose Patients Withdrawals Outcomes Results Trial measured quality (Jadad) Sawa and DB crossover Baclofen increasing N = 21. N=3 Spasticity was assessed On baclofen, 13/18 patients 3/5 Paty (1979), RCT 10–60 mg/day. 6 F, 15 M. using the researchers’ showed an objective Canada11 Placebo. Mean ages 36 (F) and own grading scale, improvement in spasticity Treatment for 3 weeks, 49 (M) y. which ranged from 0 to (p < 0.001). washout period of 7 All patients had clinically 5, where 0 represents No change on placebo. days followed by 2nd definite or presumed ‘no spasticity’ and 5 intervention MS. represents ‘ in the The incidence of side-effects Mean duration of MS absence of voluntary was high, 71% of those on 9 y (female), contraction, the leg will baclofen had side-effects 14 y (male). stay extended for a compared with 19% on Median spasticity 3 on period of 30 s or more’ placebo. Common side-effects ad hoc scale of 0–5 were sedation, nausea and vomiting Brar et al. DB crossover Baclofen alone N = 38. N = 8, due to Quadriceps Significant improvement 2/5 (1991), RCT 20 mg/day. Aged 24–54 y. exacerbation of hypertonicity based on (p < 0.05) on both baclofen USA17 Placebo alone. 9 M, 29 F. symptoms (n = 4), Cybex flexion scores. treatment and combination Baclofen + stretching. Clinically definite MS. transportation (Muscle tone.) therapy when compared with Placebo + stretching. Duration of disease not difficulties (n = 2), Ashworth score. placebo. Difference between 2 weeks on each stated. side-effects (n = 1) and Self-assessed functional baclofen and combination Health Technology Assessment 2003; Vol. 7: No. 40 treatment. Only patients with an other (n = 1) ability (minimal record therapy not significant. Ten-week study EDSS score of 2 months. All had moderately severe Side-effects: more muscle spasticity. weakness experienced by those Spasticity ‘interfered with on baclofen (statistically significant activities of daily living’ at 0.01); patients reported no difference in tolerability between drugs, physicians and physiotherapists reported tizanidine better tolerated than Health Technology Assessment 2003; Vol. 7: No. 40 baclofen Hoogstraten ‘Partially blind’ Dosage titrated over N = 16. N=5 Kurztke EDSS. Overall, both drugs noted to be 3/5 et al. (1988), randomised, 2–3 weeks, then held All with MS. Incapacity status. effective, with no significant The crossover for 4 weeks. All with spasticity for AMB. difference between them. Netherlands31 study 3 day washout. >2 months. Ashworth scale. Baclofen dose ranged Patient-evaluated overall Muscular weakness reported in 10 M, 6 F. from 15 to 60 mg daily, spastic condition, 6 patients on baclofen, none on Scored 4–7 on EDSS tizanidine from 12 to impairment of activities, tizanidine. 24 mg daily overall disability status, Of the five withdrawals, one etc. started on baclofen and withdrew ‘Based on these … the because of falls due to weakness, efficacy and tolerance of one started on tizanindine and the treatment were withdrew because of depression, evaluated …’ three started on tizanidine, then withdrew in second treatment period on baclofen because of falls 31 32 TABLE 9 Tizanidine vs baclofen vs tetrazepam Results of the systematic review of treatments for spasticity in MS Study Design Drugs and dose Patients Withdrawals Outcomes Results Trial measured quality (Jadad) Pellkofer DB parallel Tizanidine 2-mg N = 47. 3 dropouts in the Kurtzke scale. Spasticity reduced on all three 4/5 et al. (1989), group RCT capsules, n = 15. All with MS >2 y duration, baclofen and Pedersen scale. drugs, but no differences between Germany33 Baclofen 5-mg capsules, stable for >2 months. tizanidine groups Ashworth score. them in terms of effectiveness. n = 16. due to Zerlsen health status 18 M, 29 F. Side-effects: tizanidine 3 Tetrazepam 25-mg ineffectiveness! scale. hypotonia, somnolence; baclofen, capsules, n = 16. Aged 18–65 y Dotes scale 1 weakness, somnolence, Number (dose) taken dizziness; tetrazepam, not specified. 3 weakness, dizziness, 35 days treatment somnolence  Health Technology Assessment 2003; Vol. 7: No. 40 32 and 61 dropouts, respectively. Tizanidine was with a high proportion moderately or severely given in doses up to 36 mg daily. In both cases the affected and in the largest trial the majority were primary outcome measure was a variant of the bedridden. Ashworth score (not measured in the same way in both studies). In the larger study, the frequency of Outcome was assessed using a variety of measures, muscle spasms and clonus was also used as a including the Ashworth score, the Kurtzke and primary outcome measure. Pedersen functional assessment scales, and investigator, physiotherapist and patient One study showed a reduction in muscle tone on preference. Overall, there was no difference treatment that was significantly greater than between the two drugs on any of the outcomes placebo, the other did not. In the former study, assessed, with the exception of one study37 which the baseline muscle tone in the placebo group was reported a significant improvement in the slightly lower than in the treated group. It should combined Ashworth score for four lower limb be noted that the summation and averaging of the joints on tizanidine but not on baclofen. Moreover, Ashworth scores for individual muscle groups (the in the three of the four studies which assessed basis on which efficacy was claimed) was functional improvement using the Kurtzke and statistically inappropriate, as it is measured on an Pedersen scales, neither drug produced any ordinal scale. In the latter, the muscle tone was improvement in functional status. slightly higher in the placebo group at baseline, and the fall on placebo was greater than expected. Comparison with baclofen and In this study, which assessed muscle spasm and tetrazepam clonus as a primary outcome measure, there was a One study consisted of a three-way comparison greater reduction in spasms and clonus in the between tizanidine, baclofen and tetrazepam.33 treated than in the placebo group. A non- Unfortunately, although the capsule strength is significant trend towards this was reported in the stated, the number of capsules (and hence total other study. Neither study demonstrated any dose) taken by each patient is not explicit. There difference in functional status between the placebo were three dropouts (out of 16 and 15 patients) in and treatment groups. each of the baclofen and tizanidine groups due to ineffectiveness of the treatment. Spasticity is The third placebo-controlled RCT of prolonged reported to have been reduced in each of the tizanidine use reported no significant difference three groups, but there was no difference between between active drug and placebo in Kurtzke EDSS them in terms of effectiveness. score, AMB, ‘upper extremity index’ muscle strength or electrophysiological parameters. Side-effects However, there was significant improvement in Overall, tizanidine is well tolerated. The most limb tone, tendon reflexes and in the overall frequent side-effects mentioned are drowsiness assessment made by the investigators in the drug- and a dry mouth. In general, a reduction in treated as compared with the placebo group.36 spasticity was not achieved at the expense of muscle strength. Tizanidine was better tolerated Comparison with diazepam than diazepam, but there appeared to be little One study compared tizanidine with diazepam in difference between it and baclofen in terms of MS patients. Thirty patients were treated with frequency and severity of side-effects. However, in tizanidine (mean dose 14.3 mg) or diazepam the only study where individual overall preferences (mean dose 15.0 mg) for 6 weeks. Clinical effect is were assessed, patients, investigators and said to have been assessed using Ashworth score, physiotherapists preferred baclofen over although how this was done is not explicit. Overall tizanidine. there was no difference between the two drugs. Summary Comparison with baclofen Tizanidine is effective in both the short and Six studies compared tizanidine with baclofen, medium term, in comparison with placebo. When including the ‘partially blind’ study. The study compared with diazepam or baclofen, tizanidine sizes varied from 16 to 100 patients, with between appears to be equally effective. Whilst tizanidine 0 and 18 dropouts. Tizanidine dosage was in the has a significant effect on muscle tone, frequency range 6–36 mg daily, for a duration of 6–8 weeks. of spasms and clonus, it has not been shown to Two were crossover studies. The severity of have an effect in terms of functional ability. spasticity of patients in these trials appears to have However, in view of the relatively small sample been greater than in the placebo controlled trials, sizes of these studies, there may be a real 33 © Queen’s Printer and Controller of HMSO 2003. All rights reserved.  Results of the systematic review of treatments for spasticity in MS difference in effect that has been missed (Type II duration of disease were not stated. The study error). Most of the studies show no difference comparing diazepam with tizanidine again between tizanidine and its comparators in terms of recruited only MS patients with mean disease causing muscle weakness. Only two studies found duration 9 years (basis of diagnosis not stated). that tizanidine is less likely to cause muscle The mean age was 41 years, with 19 women and weakness than alternative drug therapy.31,38 11 men. Spasticity was described as ‘moderate to severe’, but the extent of disability was not otherwise stated. Diazepam Of the two trials comparing diazepam with